Polymorph of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto

ABSTRACT

Polymorph Form III of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide, and use thereof as a sedative-hypnotic, anxiolytic, anticonvulsant, and/or skeletal muscle relaxant agent. Related compositions and methods are also disclosed, particularly with regard to treatment of insomnia.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/406,072 filed Aug. 26, 2002, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is generally directed to a novel polymorph ofN-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamidewhich has activity over a wide range of indications, and is particularlyuseful for the treatment of insomnia, and to related processes,compositions and methods.

2. Description of the Related Art

The term “insomnia” is used to describe all conditions related to theperception of inadequate or non-restful sleep by the patient (Dement,International Pharmacopsychiatry 17:3-38, 1982). If left untreated,insomnia may result in disturbances in metabolism and overall bodyfunction including reduced productivity and significant changes in mood,behavior and psychomotor function, and a higher incidence of morbidityand mortality.

Traditionally, the management of insomnia includes treatment and/ormitigation of the etiological factors, improving sleep hygiene and theadministration of hypnotic agents. The early hypnotic agents, such asbarbiturates, while effective, elicited a spectrum of unwanted sideeffects and longer-term complications. For example, barbiturates havethe potential to result in lethargy, confusion, depression and a varietyof other residual effects many hours post dosing, as well as having apotential for being highly addictive.

During the 1980's, the pharmaceutical treatment of insomnia shifted awayfrom barbiturates and other CNS depressants toward the benzodiazepineclass of sedative-hypnotics. This class of sedative-hypnotic agentsshowed substantial effectiveness in producing a calming effect whichresults in sleep-like states in man and animals (Gee et al., Drugs inCentral Nervous Systems, Horwell (ed.), New York, Marcel Dekker, Inc.,1985, p. 123-147) and had a greater safety margin than prior hypnotics,barbiturates or chloral hydrate (Cook and Sepinwall, Mechanism of Actionof Benzodiazepines, Costa and Greengard (eds.), New York, Raven Press,1975, p. 1-28). As with barbiturates, however, many benzodiazepines alsopossess side effects that limit their usefulness in certain patientpopulations. These problems include synergy with other CNS depressants(especially alcohol), the development of tolerance upon repeat dosing,rebound insomnia following discontinuation of dosing, hangover effectsthe next day, and impairment of psychomotor performance.

More recently, a new class of agents has undergone development. Theseagents are non-benzodiazepine compounds, which bind selectively to aspecific receptor subtype of the benzodiazepine receptor. This receptorselectivity is thought to be the mechanism by which these compounds areable to exert a robust hypnotic effect, while also demonstrating animproved safety profile relative to the non-selective, benzodiazepineclass of agents. The first of these agents to be approved by the UnitedStates Food and Drug Administration (FDA) for marketing in the UnitedStates was Ambien (zolpidem tartrate), which is based on theimidazopyridine backbone (see U.S. Pat. Nos. 4,382,938 and 4,460,592).In addition to Ambien, another compound known as Sonata (zaleplon),which is a pyrazolopyrimidine-based compound, has received FDA approval(see U.S. Pat. No. 4,626,538). Other non-benzodiazepine compounds and/ormethods for making or using the same have also been reported (see, e.g.,U.S. Pat. No. 4,794,185, 4,808,594, 4,847,256, 5,714,607, 4,654,347;5,891,891).

While significant advances have been made in this field, there is stilla need in the art for compounds that are effective as sedative orhypnotic agents generally, particularly in the context of treatinginsomnia. One such compound isN-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide(referred to herein as “Compound 1”). Compound 1 is disclosed in U.S.Pat. No. 6,399,621 and has the following chemical structure:

In addition, U.S. Pat. Nos. 6,384,221 and 6,544,999 are directed topolymorph Form I and Form II of Compound 1, while U.S. Pat. Nos.6,472,528 and 6,485,746 are directed to synthesis and controlledrelease, respectively, of Compound 1.

While Compound 1 has proven particularly promising for the treatment ofinsomnia, improved forms of this compound are desired, particularly withregard to enhanced solubility, oral bioavailability, ability to bereadily formulated, ease of synthesis, and/or physical stability. Thepresent invention fulfills one or more of these needs and providesfurther related advantages.

BRIEF SUMMARY OF THE INVENTION

The present invention is generally directed to a novel polymorphic formof Compound 1, referred to herein as “polymorph Form III”. PolymorphForm III exhibits a predominant endotherm peak at about 191° C. (asmeasured by a TA 2920 Modulated Differential Scanning Calorimeter (DSC)at a scan rate of 10° C. per minute). Polymorph Form III also exhibitsan X-ray Powder Diffraction pattern with characteristic peaks (expressedin degrees 2θ (+/−0.2°θ) at one or more of the following positions:10.2, 13.3, 18.9, 20.7, 22.2, 28.1 and 30.8. More specifically, suchcharacteristic peaks are at 18.9 and 28.1, and further at 10.2, andfurther at 13.3, 20.7, 22.2 and 30.8.

Polymorph Form III has utility over a wide range of applications,including utility as a sedative and/or hypnotic agent generally and,more specifically, for the treatment of insomnia. Thus, in anotherembodiment, methods are disclosed for treating various conditions,including insomnia, by administering an effective amount of polymorphForm III to an animal or subject in need thereof (referred to herein asa “patient”), and typically to a warm-blooded animal (including ahuman).

In one embodiment, polymorph Form III is substantially pure—that is,containing less than 2% by weight total impurities, less than about 1%by weight water, and less than 0.5% by weight residual organic solvent;or, in a more specifically embodiment, less than 1% by weight totalimpurities, less than about 0.75% by weight water, and less than 0.4% byweight residual organic solvent.

In another embodiment, Compound 1 is in the form of a composition ormixture of polymorph Form III along with one or more other crystalline,solvate, amorphous, or other forms of Compound 1. For example, such acomposition may comprise polymorph Form III along with one or more otherpolymorphic forms of Compound 1, such as polymorph Form I and/or FormII. More specifically, the composition may comprise from trace amountsup to 100% polymorph Form III, or any amount in between—for example, thecomposition may comprise less than 0.1%, 0.5%, 1%, 2%, 5%, 10%, 20%,30%, 40% or 50% by weight of polymorph Form III based on the totalamount of Compound 1 in the composition. Alternatively, the compositionmay comprise at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%or 99.9% by weight of polymorph Form III based on the total amount ofCompound 1 in the composition.

Prior to administration, and in further embodiment, polymorph Form IIImay be formulated as a pharmaceutical composition that contains aneffective dosage amount of polymorph Form III in combination with one(or more) pharmaceutically acceptable carrier(s). Such compositions mayassume a variety of forms, including pills, tablets and capsules fororal administration.

In still another embodiment, the pharmaceutical composition comprises aneffective dosage amount of Compound 1, wherein Compound 1 comprises atleast a certain percentage of polymorph Form III (based on the totalamount of Compound 1 present in the composition—that is, the totalamount of Compound 1 being 100%). In other words, at least a certainpercentage of Compound 1 present within the pharmaceutical compositionexists as polymorph Form III, with the remainder of Compound 1 being ina different form, including (but not limited to) polymorph Form I,polymorph Form II, or any other crystalline, solvate or amorphousform(s).

In yet a further embodiment, this invention provides processes formaking polymorph Form III. For example, polymorph Form III may be madeby (a) providing a heated crystallization solvent comprising Compound 1,(b) adding water and a nucleating agent (such as carbon or crystals ofpolymorph Form III) thereto in amounts sufficient to inducecrystallization of polymorph Form III, and (c) collecting crystallizedpolymorph Form III. Optionally, the crystallization solvent can becooled after step (b). In an alternative embodiment, polymorph Form IIImay be made by (a) providing a heated crystallization solvent comprisingCompound 1, (b) adding the heated crystallization solvent to aco-solvent or mixture of co-solvents, (c) adding a nucleating agentthereto in amounts sufficient to induce crystallization of polymorphForm III, and (d) collecting crystallized polymorph Form III. Further,polymorph Form III made according to one or more of the processes ofthis invention is also disclosed.

These and other aspects of this invention will be apparent uponreference to the following detailed description and attached figures. Tothat end, certain patent and other documents are cited herein to morespecifically set forth various aspects of this invention. Each of thesedocuments is hereby incorporated by reference in its entirety.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a Differential Scanning Calorimetry (DSC) thermogram ofpolymorph Form III.

FIG. 2 is an X-ray powder diffraction spectrum of polymorph Form III.

FIG. 3 is an Raman FT Infrared spectrum of polymorph Form III.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention is generally directed to anovel polymorphic form of Compound 1, referred to herein as “polymorphForm III”, as well as to compositions containing the same. Alsodisclosed are methods relating to the use of polymorph Form III byadministration to a patient in need of the same, and to processes formaking polymorph Form III.

Solids exist in either amorphous or crystalline forms. In the case ofcrystalline forms, molecules are positioned in 3-dimensional latticesites. When a compound recrystallizes from a solution or slurry, it maycrystallize with different spatial lattice arrangements, a propertyreferred to as “polymorphism,” with the different crystal formsindividually being referred to as a “polymorph”. Different polymorphicforms of a given substance may differ from each other with respect toone or more physical properties, such as solubility and dissociation,true density, crystal shape, compaction behavior, flow properties,and/or solid state stability. In the case of a chemical substance thatexists in two (or more) polymorphic forms, the unstable forms generallyconvert to the more thermodynamically stable forms at a giventemperature after a sufficient period of time. When this transformationis not rapid, the thermodynamically unstable form is referred to as the“metastable” form. In general, the stable form exhibits the highestmelting point, the lowest solubility, and the maximum chemicalstability. However, the metastable form may exhibit sufficient chemicaland physical stability under normal storage conditions to permit its usein a commercial form. In this case, the metastable form, although lessstable, may exhibit properties desirable over those of the stable form,such as enhanced solubility or better oral bioavailability.

In the case of Compound 1, two polymorphic forms (i.e., Form I and FormII) have previously been reported (see U.S. Pat. Nos. 6,384,221 and6,544,999). Compound 1 is presently undergoing clinical trials fortreatment of insomnia. In anticipation of potential large-scaleproduction, significant effort has been directed to the commercial-scaleproduction of Compound 1. During one such production run, an impuritywas discovered within the end product. In an effort to remove theimpurity, carbon was added, followed by recrystallization. As a resultof this subsequent work up, it was surprisingly discovered that a newpolymorph (i.e., polymorph Form III) was obtained. While not intendingto be limited by theory, it is believed that the added carbon served asa nucleation site for formation of polymorph Form III.

The novel and surprising polymorph of this invention, polymorph FormIII, may be characterized by, for example, melting point and/or X-Raypowder diffraction spectrometry. As shown in FIG. 1, polymorph Form IIIexhibits a predominant endotherm peak at about 191° C. as measured by aTA 2920 (TA Instruments, New Castle, Del.) Modulated DifferentialScanning Calorimeter (DSC) at a scan rate of 10° C. per minute with anIndium standard. As used herein, the term “about 191° C.” means a rangeof 190 to 192.5° C. In this regard, it should be understood that theendotherm measured by a particular differential scanning calorimeter isdependent upon a number of factors, including the rate of heating (i.e.,scan rate), the calibration standard utilized, instrument calibration,relative humidity, and upon the chemical purity of the sample beingtested. Thus, an endotherm as measured by DSC on the instrumentidentified above may vary by as much as ±1° C. or even ±1½° C.Accordingly, the term “about 191° C.” is intended to encompass suchinstrument variations.

The X-Ray powder diffraction spectrum for polymorph Form III ispresented in FIG. 2, and is set forth in tabular form in Table 1 below.The X-Ray powder diffraction was measured by a Siemens D500 AutomatedPowder Diffractometer equipped with graphite monochromator and a Cu(λ=1.54 Angstrom) X-ray source operated at 50 kV, 40 mA. Two-thetacalibration is performed using an NBS mica standard. The sample wasanalyzed using the following instrument parameters: measuringrange=4-40° 2θ; step width=0.050°; and measuring time per step=1.2 sec.

TABLE 1 X-Ray Powder Diffraction Spectral Lines d value 2-θ° IntensityIntensity % 9.15587 9.652 1388 7.0 8.91589 9.912 7718 39.1 8.6567010.210 19744 100.0 8.16181 10.831 572 2.9 7.88947 11.206 1398 7.16.85166 12.910 765 3.9 6.64840 13.306 4690 23.8 6.29329 14.061 396 2.05.24469 16.891 1398 7.1 5.19705 17.047 1731 8.8 5.05094 17.544 1170 5.94.76647 18.600 1567 7.9 4.69634 18.880 4865 24.6 4.34978 20.400 1131 5.74.29694 20.654 4611 23.4 4.12546 21.522 758 3.8 4.00186 22.195 2281 11.63.87889 22.908 1046 5.3 3.72796 23.849 321 1.6 3.56593 24.950 752 3.83.51637 25.307 716 3.6 3.40208 26.172 781 4.0 3.34446 26.631 1738 8.83.30597 26.947 764 3.9 3.23885 27.516 544 2.8 3.17029 28.124 4022 20.43.01819 29.572 480 2.4 2.97878 29.973 264 1.3 2.89811 30.827 2802 14.22.79651 31.977 890 4.5 2.77443 32.238 354 1.8 2.60380 34.415 407 2.12.53630 35.360 1434 7.3 2.41973 37.124 262 1.3 2.38437 37.695 253 1.3

The crystal structure of polymorph Form III was determined by singlecrystal X-ray diffraction analysis. A colorless plate of polymorph FormIII having dimensions of 0.30×0.20×0.13 mm was mounted on a glass fiberin random orientation. Preliminary examination and data collection wereperformed with Mo K_(α) radiation (λ=0.71073 Å) on a Nonius KappaCCDdiffractometer. Data relating to the single crystal X-raycrystallography of polymorph Form III is presented in the followingTables 2-6.

TABLE 2 Crystal Parameters Space Group P2₁/n a, Å  9.5887(3) b, Å 10.3985(4) c, Å  17.5807(7) α  90 β  96.8044(14) γ  90 Z(molecules/unit cell)  4 Calculated Density (g/cm)  1.436 Temperature(K) 150

TABLE 3 Positional Parameters and Their Estimated Standard DeviationsAtom x y z U (Å²) S(1) 0.46180(7) −0.27982(8)  0.14578(4) 0.0384(2) O(6)0.62938(19) −0.0547(2)  0.18402(10) 0.0382(6) O(122) 0.8323(3) 0.2180(3) −0.36178(12) 0.0643(8) N(8) 0.7964(2)  0.1011(2)  0.09047(13)0.0405(7) N(9) 0.8076(2)  0.1723(2)  0.15438(12) 0.0317(6) N(14)0.8428(2)  0.0463(2) −0.03115(11) 0.0286(6) N(12A) 0.9717(5)  0.2278(5)−0.2546(3) 0.0282(12) N(12B) 0.9122(5)  0.3116(5) −0.2521(3) 0.0319(14)C(2) 0.3830(3) −0.3736(3)  0.07383(18) 0.0420(9) C(3) 0.4087(3)−0.3309(3)  0.00378(17) 0.0391(8) C(4) 0.4960(3) −0.2230(3)  0.00787(16)0.0331(7) C(5) 0.5358(2) −0.1829(3)  0.08160(14) 0.0294(7) C(6)0.6305(2) −0.0805(3)  0.11554(13) 0.0280(7) C(7) 0.7219(2) −0.0121(2) 0.06857(13) 0.0264(7) C(10) 0.8880(3)  0.2745(3)  0.15515(15) 0.0333(7)C(11) 0.9616(3)  0.3131(3)  0.09337(14) 0.0311(7) C(12) 0.9484(2) 0.2422(3)  0.02666(14) 0.0269(6) C(13) 0.8667(2)  0.1337(2) 0.02781(11) 0.0154(5) C(15) 0.7574(3) −0.0389(3) −0.00555(14) 0.0289(7)C(121) 1.0127(3)  0.2801(2) −0.04226(14) 0.0272(7) C(122) 1.1408(2) 0.3451(2) −0.03341(14) 0.0278(7) C(123) 1.2019(3)  0.3852(3)−0.09671(14) 0.0292(7) C(124) 1.1380(3)  0.3615(3) −0.17015(16)0.0412(8) C(125) 1.0100(4)  0.2988(4) −0.17857(16) 0.0614(11) C(126)0.9462(3)  0.2586(3) −0.11575(16) 0.0453(8) C(12A) 0.8662(6)  0.2827(7)−0.3016(3) 0.0324(17) C(12B) 0.9236(7)  0.2085(7) −0.2969(4) 0.0361(17)C(13A) 1.0305(3)  0.1070(3) −0.27368(17) 0.0446(9) C(13B) 0.8135(3) 0.4141(3) −0.27623(17) 0.0430(9) H(2) 0.328 −0.447  0.082 0.050 H(3)0.371 −0.370 −0.043 0.047 H(4) 0.525 −0.182 −0.036 0.040 H(10) 0.898 0.326  0.200 0.040 H(11) 1.020  0.387  0.098 0.037 H(15) 0.723 −0.112−0.034 0.035 H(122) 1.186  0.362  0.016 0.033 H(123) 1.289  0.430 −0.0900.035 H(124) 1.181  0.388 −0.214 0.049 H(126) 0.857  0.217 −0.123 0.055U_(eq) = (1/3) Σ_(i)Σ_(j) U_(ij)a*_(i)a*_(j)a_(i) · a_(j) Hydrogensincluded in calculation of structure factors but not refined.

TABLE 4 Anisotropic Temperature Factor Coefficients Name U(1, 1) U(2, 2)U(3, 3) U(1, 2) U(1, 3) U(2, 3) S(1) 0.0396(4) 0.0424(5) 0.0333(4)−0.0081(3) 0.0048(3) 0.0054(3) O(6) 0.0505(11) 0.0416(12) 0.0240(10)−0.0064(9) 0.0105(8) −0.0006(8) O(122) 0.0705(15) 0.096(2) 0.0248(11)−0.0246(14) −0.0014(10) −0.0111(12) N(8) 0.0482(14) 0.0424(15)0.0313(13) 0.0033(11) 0.0067(10) 0.0017(11) N(9) 0.0430(12) 0.0308(13)0.0220(11) 0.0035(10) 0.0067(9) −0.0032(9) N(14) 0.0346(11) 0.0299(12)0.0215(10) −0.0007(9) 0.0039(8) −0.0037(9) N(12A) 0.035(2) 0.035(3)0.013(2) 0.000(2) −0.0042(19) 0.0008(19) N(12B) 0.035(2) 0.036(3)0.024(3) 0.005(2) 0.0010(19) 0.006(2) C(2) 0.0354(14) 0.0386(18)0.0512(19) −0.0088(12) 0.0014(12) 0.0004(14) C(3) 0.0359(15) 0.0408(18)0.0386(16) −0.0010(12) −0.0037(11) −0.0033(13) C(4) 0.0315(13)0.0382(17) 0.0288(14) 0.0034(11) −0.0002(10) −0.0007(12) C(5) 0.0295(13)0.0312(15) 0.0275(13) 0.0042(10) 0.0036(10) 0.0036(11) C(6) 0.0314(13)0.0292(14) 0.0233(13) 0.0033(10) 0.0030(9) 0.0025(10) C(7) 0.0336(13)0.0252(14) 0.0208(12) 0.0038(10) 0.0043(9) 0.0018(10) C(10) 0.0452(15)0.0324(16) 0.0228(13) −0.0004(12) 0.0061(11) −0.0033(11) C(11)0.0396(14) 0.0300(14) 0.0236(12) −0.0006(11) 0.0038(10) −0.0019(11)C(12) 0.0291(12) 0.0308(14) 0.0208(12) 0.0034(10) 0.0029(9) 0.0023(10)C(13) 0.0207(10) 0.0169(11) 0.0089(9) 0.0014(8) 0.0030(7) −0.0004(8)C(15) 0.0358(13) 0.0282(14) 0.0227(12) 0.0010(10) 0.0031(9) −0.0011(10)C(121) 0.0317(13) 0.0290(15) 0.0211(12) 0.0031(10) 0.0034(9) 0.0017(10)C(122) 0.0331(13) 0.0258(14) 0.0237(12) 0.0014(10) −0.0005(9)−0.0012(10) C(123) 0.0303(13) 0.0273(14) 0.0298(13) −0.0024(10)0.0030(10) 0.0004(11) C(124) 0.0424(15) 0.056(2) 0.0253(14) −0.0174(13)0.0041(11) 0.0038(13) C(125) 0.058(2) 0.106(3) 0.0183(15) −0.043(2)−0.0035(13) 0.0069(16) C(126) 0.0371(15) 0.074(2) 0.0232(14) −0.0218(14)−0.0028(11) 0.0084(13) C(12A) 0.029(3) 0.049(4) 0.019(3) −0.001(3)0.002(2) 0.004(3) C(12B) 0.038(3) 0.047(4) 0.024(3) −0.001(3) 0.006(3)−0.001(3) C(13A) 0.0548(18) 0.0415(18) 0.0357(16) 0.0079(13) −0.0024(12)−0.0088(13) C(13B) 0.0461(16) 0.048(2) 0.0341(15) 0.0134(13) 0.0017(12)0.0084(13) The form of the anisotropic temperature factor is: exp[−2π{h²a*²U(1, 1) + k²b*²U(2, 2) + l²c*²U (3, 3) + 2hka*b*U(1, 2) +2hla*c*U(1, 3) + 2klb*c*U(2, 3)}], where a*, b*, and c* are reciprocallattice constants.

TABLE 5 Bond Distances Atom 1 Atom 2 Distance S(1) C(2) 1.702(3) S(1)C(5) 1.727(3) O(6) C(6) 1.235(3) O(122) C(12A) 1.263(7) O(122) C(12B)1.357(8) N(8) N(9) 1.339(3) N(8) C(13) 1.400(3) N(8) C(7) 1.406(3) N(9)C(10) 1.312(4) N(14) C(15) 1.321(3) N(14) C(13) 1.377(3) C(2) C(3)1.359(4) C(3) C(4) 1.396(4) C(4) C(5) 1.372(4) C(5) C(6) 1.478(4) C(6)C(7) 1.460(3) C(7) C(15) 1.413(3) C(10) C(11) 1.421(4) C(11) C(12)1.378(4) C(12) C(13) 1.375(3) C(12) C(121) 1.477(3) C(121) C(126)1.390(4) C(121) C(122) 1.394(3) C(122) C(123) 1.382(3) C(123) C(124)1.384(4) C(124) C(125) 1.383(4) C(125) C(126) 1.389(4) C(125) N(12B)1.510(5) C(125) N(12A) 1.533(6) N(12A) C(12A) 1.355(7) N(12A) C(13A)1.432(6) C(12A) C(13B) 1.540(8) N(12B) C(12B) 1.343(8) N(12B) C(13B)1.454(5) C(12B) C(13A) 1.494(8) Numbers in parentheses are estimatedstandard deviations in the least significant digits.

TABLE 6 Bond Angles Atom 1 Atom 2 Atom 3 Angle Atom 1 Atom 2 Atom 3Angle C(2) S(1) C(5) 91.67(14) C(126) C(121) C(122) 118.9(2) C(12A)O(122) C(12B) 42.2(4) C(126) C(121) C(12) 122.0(2) N(9) N(8) C(13)121.9(2) C(122) C(121) C(12) 119.1(2) N(9) N(8) C(7) 132.9(2) C(123)C(122) C(121) 120.5(2) C(13) N(8) C(7) 105.3(2) C(122) C(123) C(124)121.0(2) C(10) N(9) N(8) 116.5(2) C(125) C(124) C(123) 118.2(3) C(15)N(14) C(13) 103.91(19) C(124) C(125) C(126) 121.7(3) C(3) C(2) S(1)112.0(2) C(124) C(125) N(12B) 120.2(3) C(2) C(3) C(4) 112.8(3) C(126)C(125) N(12B) 114.9(3) C(5) C(4) C(3) 113.0(3) C(124) C(125) N(12A)116.0(3) C(4) C(5) C(6) 133.6(2) C(126) C(125) N(12A) 117.8(3) C(4) C(5)S(1) 110.5(2) N(12B) C(125) N(12A) 40.2(2) C(6) C(5) S(1) 115.89(18)C(125) C(126) C(121) 119.6(3) O(6) C(6) C(7) 121.4(2) C(12A) N(12A)C(13A) 120.9(5) O(6) C(6) C(5) 118.3(2) C(12A) N(12A) C(125) 114.4(5)C(7) C(6) C(5) 120.3(2) C(13A) N(12A) C(125) 124.5(4) N(8) C(7) C(15)104.4(2) O(122) C(12A) N(12A) 112.7(6) N(8) C(7) C(6) 124.9(2) O(122)C(12A) C(13B) 130.8(5) C(15) C(7) C(6) 130.7(2) N(12A) C(12A) C(13B)116.4(5) N(9) C(10) C(11) 124.4(2) C(12B) N(12B) C(13B) 120.6(6) C(12)C(11) C(10) 119.7(3) C(12B) N(12B) C(125) 110.2(5) C(13) C(12) C(11)114.9(2) C(13B) N(12B) C(125) 129.1(4) C(13) C(12) C(121) 121.7(2)N(12B) C(12B) O(122) 110.2(6) C(11) C(12) C(121) 123.4(2) N(12B) C(12B)C(13A) 120.3(6) C(12) C(13) N(14) 125.07(19) O(122) C(12B) C(13A)129.5(5) C(12) C(13) N(8) 122.6(2) N(12A) C(13A) C(12B) 33.8(3) N(14)C(13) N(8) 112.3(2) N(12B) C(13B) C(12A) 37.9(3) N(14) C(15) C(7)114.1(2) Numbers in parentheses are estimated standard deviations in theleast significant digits.

In addition, FIG. 3 shows the FT-Raman spectra of polymorph Form III asacquired on a Raman accessory module interfaced to a Magna 860® Fouriertransform infrared (FT-IR) spectrophotometer (Thermo Nicolet). Thismodule uses an excitation wavelength of 1064 nm and an indium galliumarsenide (InGaAs) detector. Approximately 0.5 W of Nd:YVO₄ laser powerwas used to irradiate the sample. The samples were prepared for analysisby placing the material in a glass tube and positioning the tube in agold-coated tube holder in the accessory. A total of 256 sample scanswere collected from 3600-100 cm⁻¹ at a spectral resolution of 4 cm⁻¹,using Happ-Genzel apodization. Wavelength calibration was performedusing sulfur and cyclohexane.

Polymorph Form III may be prepared by crystallization from acrystallization solvent containing Compound 1. As used herein, the term“crystallization solvent” means a solvent or combination of solventsfrom which Compound 1 is preferentially crystallized as polymorph FormIII. Representative crystallization solvents include polar solvents,nonpolar solvents, protic solvents and aprotic solvents, and morespecifically include acetic acid, methylene chloride, acetone, methanol,ethanol, propanol, butanol, ethyl acetate, THF, DMF, diethyl ether,acetonitrile, toluene, water, and combinations thereof. In oneembodiment, the crystallization solvent comprises acetic acid, to whichwater is gradually added.

Compound 1 may be introduced into the crystallization solvent in eithera solid or liquid form. When added as a solid, Compound 1 may be in theform of a solid powder or any other solid form that aids its dissolutionwithin the crystallization solvent. When added as a liquid, Compound 1may first be dissolved in a co-solvent to yield a co-solvent solution,which is then combined with the crystallization solvent. Theconcentration of Compound 1 within the co-solvent solution may rangefrom 0.1% by weight to the saturation point. This concentration will, ofcourse, vary depending upon the temperature at which the co-solventsolution is held, with warmer temperatures generally allowing for thepreparation of more concentrated solutions of Compound 1. In general,the co-solvent should aid in the dissolution of Compound 1, but notnegatively interfere with the formation of polymorph Form III from theresulting crystallization solvent. Suitable co-solvents include the samesolvents as identified above for the crystallization solvent. Further,the co-solvent and the crystallization solvent may be the same ordifferent. For example, both the crystallization solvent and theco-solvent may be acetic acid, or they may be different solvents (orcombinations thereof).

In one embodiment, the co-solvent solution containing Compound 1 isadded to the crystallization solvent or, alternatively, thecrystallization solvent is added to the co-solvent solution. In stillanother embodiment, the co-solvent solution may be at or above ambienttemperature (e.g., heated), while the temperature of the crystallizationsolvent may be below (e.g., chilled), above (e.g., heated) or at ambienttemperature. Alternatively, the co-solvent solution can undergo asolvent exchange and form a solution or heterogeneous mixture of thecrystallization solvent and Compound 1. For example, Compound 1 may bedissolved in a first solvent, followed by addition to a second solvent,and then followed by removal of all or part of the first solvent (e.g.,by distillation).

Crystallization of polymorph Form III may be achieved by addition ofcarbon or other nucleating agent to the crystallization solventcontaining Compound 1. As used herein, a “nucleating agent” means asubstance that aids in the formation of “nuclei” around which a crystalgrows. Such nuclei may occur spontaneously in a supersaturatedcrystalline solvent and then will grow into larger crystals. Formationof the nuclei may also be induced by addition of a seed crystal or bythe incidental or purposeful addition of some foreign solid matter suchas dust or activated carbon. In a specific example (see Example 1below), addition of a small amount of activated carbon to a heatedsolution of Compound 1 in acetic acid (60 mL) and water (70 mL),followed by subsequent cooling steps, yields polymorph Form III. Thecarbon may be added either before or after the addition of the water toresult in formation of polymorph Form III.

Once obtained, crystals of polymorph Form III may be used as thenucleating agent or “seed” crystals for subsequent crystallizations ofpolymorph Form III from the crystallization solvent. In one embodiment,the crystallization solvent is formed by dissolving Compound 1 in hotacetone or other suitable crystallization solvent. The crystallizationsolvent is then seeded with crystals of polymorph Form III, cooled andfiltered, resulting in polymorph Form III. In another embodiment, acrystallization solvent is formed by slurrying Compound 1 in acetone orother appropriate solvent. The crystallization solvent is then seededwith crystals of polymorph Form III and filtered, resulting in polymorphForm III. Such seeding with crystals of polymorph Form III may takeplace at any time during the slurrying process. Alternatively, seedingwith crystals of polymorph Form III may take place prior to, orsimultaneously with, addition of Compound 1 to the crystallizationsolvent.

Crystals of polymorph Form III may also be used as the nucleating agentor seed crystals in the conversion of a suspension or slurry of Compound1 to produce polymorph Form III. Depending upon factors such astemperature, solvent and time, the resulting Compound 1 may bepredominantly polymorph Form III, or may be polymorphic mixtures ofCompound 1.

For purposes of administration to a patient, polymorph Form III may beformulated as a pharmaceutical composition. Such pharmaceuticalcompositions comprise polymorph Form III and one or morepharmaceutically acceptable carriers, wherein the polymorph is presentin the composition in an amount that is effective to treat the conditionof interest. Typically, the pharmaceutical compositions of the presentinvention include polymorph Form III in an amount ranging from 0.1 mg to250 mg per dosage depending upon the route of administration, and moretypically from 1 mg to 60 mg. Appropriate concentrations and dosages canbe readily determined by one skilled in the art.

Pharmaceutically acceptable carriers are familiar to those skilled inthe art. For compositions formulated as liquid solutions, acceptablecarriers include saline and sterile water, and may optionally includeantioxidants, buffers, bacteriostats and other common additives. Thecompositions can also be formulated as pills, capsules, granules, ortablets which contain—in addition to polymorph Form III—diluents,dispersing and surface-active agents, binders, lubricants, and/ordelayed releases agents. One skilled in this art may further formulatethe polymorph in an appropriate manner, and in accordance with acceptedpractices, such as those disclosed in Remington's PharmaceuticalSciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990(incorporated herein by reference in its entirety).

In another embodiment, the invention provides a method for treatingconditions that benefit from administration of agents that possessanxiolytic, anti-anoxic, sleep-inducing, hypnotic, anticonvulsant,and/or skeletal muscle relaxant properties. Such conditions includeinsonmia specifically, as well as sleep disorders generally and otherneurological and psychiatric complaints, anxiety states, vigilancedisorders, such as for combating behavioral disorders attributable tocerebral vascular damage and to the cerebral sclerosis encountered ingeriatrics, epileptic vertigo attributable to cranial trauma, and formetabolic encephalopathies.

The methods of this invention include systemic administration ofpolymorph Form III, preferably in the form of a pharmaceuticalcomposition. As used herein, systemic administration encompasses bothoral and parenteral methods of administration. For oral administration,suitable pharmaceutical compositions include powders, granules, pills,tablets and capsules, as well as liquids, syrups, suspensions andemulsions. These compositions may also include flavorants,preservatives, suspending, thickening and emulsifying agents, and otherpharmaceutically acceptable additives. For parental administration, thecompounds of the present invention can be prepared in aqueous injectionsolutions that may contain buffers, antioxidants, bacteriostats and/orother additives commonly employed in such solutions.

The following examples are offered by way of illustration, notlimitation.

EXAMPLE 1 Representative Synthesis of Polymorph Form III

Compound 1 (10 g) made according to the procedures of U.S. Pat. No.6,399,621 (incorporated herein by reference) was dissolved in 60 mL ofacetic acid. The solution was then filtered and heated to 70-75° C.Water (70 mL) and carbon (Darco G-60, 5 mg) were added to the heatedsolution, and the resulting solution was then cooled 5° C. every 30minutes. At 55° C., crystallization began and the temperature was heldsteady for 30 minutes. The mixture was then cooled to 45-50° C. and 40mL of water was added. The mixture was further cooled to 25° C. over a 1hour period and the resulting solid was filtered and washed with 40 mLof water and dried to yield 9 g of polymorph Form III as a yellow solid(see FIGS. 1 and 2 for characterization of Polymorph Form III by DSC andX-ray powder diffraction).

EXAMPLE 2 Representative Synthesis of Polymorph Form III

Compound 1 (10 g) made according to the procedure of U.S. Pat. No.6,399,621 was dissolved in 60 mL of acetic acid. The solution was thenfiltered and heated to 70-75° C. Water (70 mL) was added to the heatedsolution. After cooling to 67° C., polymorph Form III seed crystals (asobtained by the procedure described in Example 1 above) were added andthe mixture was cooled to 50° C. over 2 hours. 40 mL of water was addedand the mixture was cooled to room temperature. The resulting solid wasfiltered and washed with 40 mL of water to yield 9 g of polymorph FormIII as a yellow solid (DSC endotherm peak at 191.86° C.).

EXAMPLE 3 Representative Synthesis of Polymorph Form III

Compound 1 (10 g) was prepared according to the procedure of U.S. Pat.No. 6,399,621 and dissolved in 60 mL of acetic acid. The solution wasthen filtered and heated to 70-75° C. Water (70 mL) was added to theheated solution. After cooling to 52° C., polymorph Form III seedcrystals (as obtained by the procedure described in Example 1) wereadded and the mixture was stirred for 30 minutes. The mixture was thencooled to 47° C. over 30 minutes followed by addition of 40 mL of water.Following cooling to room temperature, the resulting solid was filteredand washed with 40 mL of water to yield 9 g of polymorph Form III as ayellow solid (DSC endotherm peak at 191.68° C.).

EXAMPLE 4 Interconversion of Compound 1

Interconversion experiments were carried out to evaluate thethermodynamic stability of Compound 1 at room temperature. Threeslurries were prepared by making saturated isopropanol solutions ofCompound 1, filtering the solutions through 0.2 μm filters, and thenadding an amount (in the form of crystals) of a polymorphic form ofCompound 1. To the first slurry, equal amounts of both polymorph Form IIand polymorph Form III (i.e., approximately 25 mg each) were added; tothe second slurry, equal amounts of polymorph From I and polymorph FormIII (i.e., approximately 25 mg each) were added; and to the thirdslurry, approximately 25 mg of polymorph Form III was added. Theslurries were then agitated for 16 days. The resulting solids werecollected by vacuum filtration, air-dried, and analyzed using XRPD. Bythe above technique, the first slurry seeded with polymorph Forms II andIII yielded exclusively polymorph Form III. On the other hand, thesecond slurry seeded with polymorph Forms I and III yielded polymorphForm III as the predominant product, with only a minor amount ofpolymorph Form I. The third slurry seeded with polymorph Form III aloneyielded exclusively polymorph Form III. These results indicate thatCompound 1, when in a slurry form, will convert to polymorph Form IIIwhen seeded with crystals of the same, and under such conditions is thefavored polymorph.

The above is a detailed description of particular embodiments of theinvention. It will be appreciated that, although specific embodiments ofthe invention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

1. Polymorph Form III ofN-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide.2. The polymorph Form III of claim 1 wherein the polymorph exhibits apredominant endotherm at about 191° C. as measured by as measured by aModulated Differential Scanning Calorimeter (DSC) at a scan rate of 10°C. per minute.
 3. The polymorph Form III of claim 1 wherein thepolymorph exhibits an X-ray powder diffraction pattern havingcharacteristic peaks expressed in degrees 2θ (+/−0.20°θ) at 18.9 and28.1.
 4. The polymorph Form III of claim 3 wherein the polymorphexhibits an additional characteristic peak expressed in degrees 2θ(+/−0.2°θ) at 10.2.
 5. The polymorph Form III of claim 4 wherein thepolymorph exhibits additional characteristic peaks expressed in degrees2θ (+/−0.2°θ) at 13.3, 20.7, 22.2 and 30.8.
 6. The polymorph Form III ofclaim 1 wherein the polymorph exhibits a single crystal x-raycrystallographic analysis at 150°K with crystal parameters as thefollowing: Space Group P2₁/n a, Å  9.5887(3) b, Å 10.3985(4) c, Å17.5807(7) α 90 β 96.8044(14) γ 90 Z (molecules/unit cell)  4 CalculatedDensity (g/cm)  1.436


7. The polymorph Form III of claim 1 wherein the polymorph contains lessthan 2% by weight total impurities, less than 1% by weight water, andless than 0.5% by weight organic solvent.
 8. The polymorph Form III ofclaim 1 wherein the polymorph contains less than 1% by weight totalimpurities, less than about 0.75% by weight water, and less than 0.4% byweight residual organic solvent.
 9. A composition comprising polymorphForm III ofN-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide.10. The composition of claim 9, further comprisingN-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamidein a crystalline, solvate or amorphous form other than polymorph FormIII.
 11. The composition of claim 9 further comprising polymorph Form I.12. The composition of claim 9 further comprising polymorph Form II. 13.A composition comprising polymorph Form III ofN-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamidein combination with a pharmaceutically acceptable carrier.
 14. Thecomposition of claim 13 wherein the composition is formulated for oraladministration.
 15. The composition of claim 14 wherein the compositionis in the form of a pill, capsule or tablet.
 16. The composition ofclaim 13 wherein polymorph Form III is present in the pill, capsule ortable in a unit dosage form in an amount from 0.1 to 250 mg.
 17. Acomposition comprising (a) polymorph Form III ofN-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide(“Compound 1”) and (b) a crystalline, solvate, amorphous or other formof Compound 1 other than polymorph Form III, wherein the total weight ofCompound 1 in the composition is the sum of (a) plus (b).
 18. Thecomposition of claim 17 wherein the composition comprises less than 0.1%by weight of polymorph Form III based on the total weight of Compound 1in the composition.
 19. The composition of claim 17 wherein thecomposition comprises less than 0.5% by weight of polymorph Form IIIbased on the total weight of Compound 1 in the composition.
 20. Thecomposition of claim 17 wherein the composition comprises less than 1%by weight of polymorph Form III based on the total weight of Compound 1in the composition.
 21. The composition of claim 17 wherein thecomposition comprises less than 2% by weight of polymorph Form III basedon the total weight of Compound 1 in the composition.
 22. Thecomposition of claim 17 wherein the composition comprises less than 5%by weight of polymorph Form III based on the total weight of Compound 1in the composition.
 23. The composition of claim 17 wherein thecomposition comprises less than 10% by weight of polymorph Form IIIbased on the total weight of Compound 1 in the composition.
 24. Thecomposition of claim 17 wherein the composition comprises less than 20%by weight of polymorph Form III based on the total weight of Compound 1in the composition.
 25. The composition of claim 17 wherein thecomposition comprises less than 30% by weight of polymorph Form IIIbased on the total weight of Compound 1 in the composition.
 26. Thecomposition of claim 17 wherein the composition comprises less than 40%by weight of polymorph Form III based on the total weight of Compound 1in the composition.
 27. The composition of claim 17 wherein thecomposition comprises less than 50% by weight of polymorph Form IIIbased upon the total weight of Compound 1 in the composition.
 28. Thecomposition of claim 17 wherein the composition comprises at least 50%by weight of polymorph Form III based upon the total weight of Compound1 in the composition.
 29. The composition of claim 17 wherein thecomposition comprises at least 60% by weight of polymorph Form III basedupon the total weight of Compound 1 in the composition.
 30. Thecomposition of claim 17 wherein the composition comprises at least 70%by weight of polymorph Form III based upon the total weight of Compound1 in the composition.
 31. The composition of claim 17 wherein thecomposition comprises at least 80% by weight of polymorph Form III basedupon the total weight of Compound 1 in the composition.
 32. Thecomposition of claim 17 wherein the composition comprises at least 90%by weight of polymorph Form III based upon the total weight of Compound1 in the composition.
 33. The composition of claim 17 wherein thecomposition comprises at least 95% by weight of polymorph Form III basedupon the total weight of Compound 1 in the composition.
 34. Thecomposition of claim 17 wherein the composition comprises at least 97%by weight of polymorph Form III based upon the total weight of Compound1 in the composition.
 35. The composition of claim 17 wherein thecomposition comprises at least 98% by weight of polymorph Form III basedupon the total weight of Compound 1 in the composition.
 36. Thecomposition of claim 17 wherein the composition comprises at least 99%by weight of polymorph Form III based upon the total weight of Compound1 in the composition.
 37. The composition of claim 17 wherein thecomposition comprises at least 99.5% by weight of polymorph Form IIIbased upon the total weight of Compound 1 in the composition.
 38. Thecomposition of claim 17 wherein the composition comprises at least 99.9%by weight of polymorph Form III based upon the total weight of Compound1 in the composition.
 39. The composition of claim 17 wherein thecomposition is in the form of a pill, capsule or tablet.
 40. Thecomposition of claim 17 wherein the composition is in the form of aslurry.
 41. A method for treating insomnia in a patient in need thereof,comprising administering to the patient an effective amount of thecomposition of claim
 13. 42. A method for inducing sleep in a patient inneed thereof, comprising administering to the patient an effectiveamount of the composition of claim 13.